SBIR-STTR Award

Although the sequence of the human genome was substantially completed a few years ago, there is still a huge need for the production of DNA sequence data. The number of organisms and individuals which may be sequenced is still significantly constrained by the lengthy time, high complexity and exorbitant costs of today's Sanger sequencing methods. Significant effort is currently going into the creation of new chemistries to read out the bases of DNA strands without the use of electrophoresis; however, the sample preparation processes to feed these sequencing systems has yet to be fully worked out and optimized. Many of the advanced sequencing methods require many millions of sets of amplified DNA fragments, with each set being comprised of millions of identical fragments. These sets are attached to a solid support which is then processed to read out the sequence; however, the generation of the array of DNA templates on a glass support currently requires a complex set of steps. In Phase I, we will examine the benefits of producing arrays of samples in an ordered format versus a random one and will produce prototype high-density ordered arrays. Successful accomplishment of the Phase I milestones and completion of subsequent Phase II and Phase III projects will result in the development of an ultra-high throughput prototype system which can produce cost-effective high-density chips for use in conjunction with advanced DNA sequencing instruments. Ultimately, this next generation of sample preparation and sequencing technologies, which can produce DNA sequence several orders of magnitude cheaper and faster than existing systems, can help to make the promise of personalized medicine a reality. Ultimately, the ability to produce very inexpensive detailed DNA sequence information for complex organisms' genomes will both lead to accelerated discoveries throughout biology and provide the basis for pharmacogenomics, a new paradigm in therapeutics wherein medicines are prescribed based on individual genotypes rather than just observed symptoms. A system which could inexpensively sequence the DNA within a specific tumor will help cancer researchers understand the mutations associated with various types of cancers and help lead to more effective treatments. Since one's genomic sequence never changes, it is likely in the future that everyone will have their genomes sequenced at birth, recorded electronically and used throughput their lifetime to customize their healthcare.

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The advent of next-generation sequencing technologies is allowing researchers to perform studies and make discoveries which previously were not economically or technically feasible. Thus far, however, higher-throughput next-generation sequencing systems are relatively expensive, have relatively long run times and produce relatively short reads thereby limiting their use for diagnostic applications. In this Phase II application, we propose to combine the novel chip fabrication techniques developed in Phase I, the innovative sequencing by synthesis chemistry exclusively licensed from Columbia University, and an automated prototype sequencing instrument to produce an advanced sequencing by synthesis system. This system will be higher throughput and significantly more cost effective than other competing next-generation technologies. During the project, high density chips will be fabricated, the sequencing instrument and chemistry will be optimized and an E. coli genome will be re-sequenced. This system will be capable of producing large amounts of quality sequence data faster and at a lower cost than any other near-term next generation sequencing system. This will make next-generation DNA sequencing technology more accessible to the broad research community. , ,

Public Health Relevance:
Ultimately, the ability to produce very inexpensive detailed DNA sequence information for complex organisms'genomes will both lead to accelerated discoveries throughout biology and provide the basis for Pharmacogenomics, a new paradigm in therapeutics wherein medicines are prescribed based on individual genotypes rather than just observed symptoms.

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